The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.
The regenerative potential of most terminally differentiated tissues is limited and diminishes with age. As a consequence, disabilities from common ailments such as bone fractures and joint degeneration are compounded with increasing age. Beyond the personal cost to the individual and their families, the accrued financial cost to the health system and the economy is also significant. Harvesting and expanding stem/progenitor cells for cell based therapy to treat common disorders in bone and cartilage is both cumbersome and impractical for large scale application and runs the risk of inappropriate tissue and scar formation at the graft site. Exogenous therapies such as BMP2 are expensive, are required in high dose and can give rise to ectopic bone formation.
Although activating resident stem/progenitor cells to help repair tissues may be an attractive option, low starting numbers of these cells is a limiting factor. Most structural tissues do not have a leading front of precursors that are ready to replace senescent, damaged or lost cells, even if they have a reserve of adult tissue resident stem cells. Reprogramming differentiated cells, triggering de-differentiation, replication and proliferation, is an alternate strategy provided this expanded pool of progenitors then follows resident cues to regenerate the cognate tissue.
The ability to regenerate large sections of the body plan is widespread in metazoan phylogeny but in adult vertebrates, limb regeneration is limited to urodele amphibians (salamanders). Limb regeneration in urodeles is dependent on plasticity of differentiated cells where mesenchymal tissues such as cartilage, muscle and connective tissue underlying the wound epidermis, lose their differentiated characteristics and adopt a blastemal cell state. The blastema is essentially a zone of mesenchymal cells that proliferate, differentiate and regenerate the limb according to the pre-determined body plan. It would be an important advance, and a development of significant clinical potential, if the regenerative response in salamanders could be replicated in mammalian cells, whereby differentiated tissues lose their identity and adopt a blastemal state, and contribute to tissue repair by regeneration in response to injury rather than by scarring.
In work leading up to the present invention, it has been determined that mesenchymal cell expansion does not necessarily need to occur by virtue of asymmetric stem cell division to provide both stem cell renewal and linear differentiation of the relevant daughter cell along the mesenchymal lineage through to terminal differentiation. Rather, expansion can be achieved by virtue of the transition of a mature somatic cell to a cell with multilineage potential, in particular a mesenchymal stem cell. Described herein is a novel means for reliably and efficiently generating, from differentiated cells, cells which exhibit multilineage potential, either in vitro or in vivo, thereby providing a valuable mechanism by which mesenchymal stem cell populations and/or somatic cells differentiated therefrom can be made available for a variety of research and clinical applications such as those requiring tissue repair and/or regeneration.